Obesity refers to excess accumulation and/or abnormal distribution of fat in body, body mass addition, and is a multifactorial chronic metabolic disease, and incidence of obesity increases year by year due to genetic factors, reduction of physical activity and so on. Obesity as a universal internal secretion metabolic disease is not only a worldwide epidemic disease threatening human health, but also closely associated with hyperlipemia, hypertension, diabetes, coronary heart disease and so on (H E Ren, et al., Drug therapy of obesity and advance thereof, Strait Pharmaceutical Journal, 2011, 23(1):88-90). Thus, prevention and treatment of obesity is very important. At present, measures for prevention and treatment of obesity mainly include dietary therapy, sports therapy, drug therapy and surgery etc. For patients with mild obesity, diet control and sports are effective; but for patients with moderate or more serious obesity, weight loss is a long process, dietary and sports therapy alone usually could not solve the problem, and drug therapy is necessary in such situations.
At present, drug for prevention and treatment of obesity are mainly appetite suppressants, especially center appetite suppressants, such as amphetamine, amfepramone, synephrine, fenfluramine, sibutramine as well as fluoxetine among antidepressants, and lipase inhibitor orlistat (trade name: Xenical), etc. However, the above drugs all have adverse reaction or toxic and side effects in different extents, such as cardiovascular system dysfunction, cardiac valves dysfunction, arrhythmia, pulmonary hypertension, respiratory system dysfunction, etc.
Phentermine (2-methyl-1-phenylpropan-2-amine) (Formula 1) is the most popular appetite suppressant developed for obese people in the US, has been approved as short-term auxiliary anti-obesity agent by FDA for a long time, and can be used in combination with exercise, change of living habit and reduction of caloric intake to achieve effects of weight loss in patients. It is a short-term neurotransmitter regulator, can help people having serious problem of body weight to correct dietary behavior, and achieve the goal of permanently remolding body figure by changing dietary habit. At present, its dosage forms used in clinic are: 8 mg tablets, 15 mg and 30 mg tablets and capsules, 18.75 mg and 37.5 mg tablets and capsules, 15 mg and 30 mg orally disintegrating tablets, and 15 mg and 30 mg sustained-release capsules. The therapeutic effects of phentermine depend on many factors such as dose, age of patients, gender, physiological and mental conditions. However, long-term use of phentermine may have risks of addiction and other adverse symptoms (increase in heart rate and blood pressure).

Topiramate (2,3,4,5-bis-O-(1-methylethylidene)-β-D-fructopyranose sulfamate) (Formula 2) is a broad spectrum nerve therapeutic agent approved by FDA in 1995, and has been used in clinic for many years for treatment of some epileptic seizures and prevention of migraine headache (E. Faught, et al., (1996) Neurology 46:1684-1690), and many documents disclosed the good therapeutic effects of topiramate in treatment of diabetes (U.S. Pat. No. 7,109,174B2 and U.S. Pat. No. 6,362,220B1), dysneuria (U.S. Pat. No. 6,908,902B2), depression (U.S. Pat. No. 6,627,653B2), mental disorders (U.S. Pat. No. 6,620,819B2), headache (U.S. Pat. No. 6,319,903B1) and hypertension (U.S. Pat. No. 6,201,010B1).

Topiramate is white crystalline powder, has a bitter taste, is freely soluble in organic solvents such as acetone, chloroform, dimethylsulfoxide and ethanol, very freely soluble in alkaline solution having pH of 9-10 such as sodium hydroxide or sodium phosphate solutions, very slightly soluble in water (room temperature) with solubility of only about 9.8 mg/m, and the pH of its saturated solution is 6.3 (Physician's Desk Reference, 56.sup.th ed., pp. 2590-2595 (2002)). Topiramate has linear pharmacokinetic features, can be rapidly and completely absorbed in vivo. After being orally taken in dose of 400 mg by healthy volunteers, it can reach an average plasma peak concentration (Cmax) within 2 h. Plasma concentration of topiramate shows linear relations with dosage in daily dose range from 100 mg to 800 mg, and has a low clearance for oral administration (22-36 ml/min) and a long plasma half-life (19-25 h). Within plasma concentration range of 0.5-250 μm/ml, topiramate has a human plasma protein binding ratio of 15-41%, which decreases with the increase of plasma concentration.
It was found recently that low dose of topiramate and low dose of phentermine in combination is effective in treatment of obesity with less adverse reactions. The main observation indexes of this compound preparation (3.75 mg phentermine/23 mg topiramate) comes up to expectations in both two phase III clinic tests named as EQU IP and CONQUER separately, in comparison with placebo, it could significantly reduce body weight in patients, and more important, the compound preparation showed good safety, it was not observed that this drug could result in QT extension or had any effects on cognition and psychological functions. There was not teratogenic case in the test, the adverse reactions were merely dry mouth and numbed fingers and toes, and these adverse reactions could be alleviated by drinking more water (Progress in Pharmaceutical Sciences, 2009, 33(12):576-577).
Topiramate has a narrow therapeutic window, because the fluctuation of plasma concentration usually results in some adverse reactions, which are symptoms mainly associated with central nervous system, such as ataxia, attention impairment, confusion, dizziness, fatigue, paresthesia, somnolence, and thinking abnormal, etc. (Physician's Desk Reference, 60th ed., pp 2538-2447(2006)). Thus, in order to improve patient compliance and effect, it is necessary to provide a once-daily dose of sustained-release preparation of topiramate in the composition of phentermine and topiramate.
CN102112126A discloses a composition comprising low-dose rapid-release phentermine and low-dose sustained-release composition of topiramate, a unit dose of the composition comprising 3.75 mg of phentermine and 23 mg of topiramate, in which, the sustained-release composition of topiramate is produced firstly by preparing topiramate drug-loaded matrix cores with 40% w/w of topiramate and 56.5% w/w of microcrystalline cellulose (AvicelPH102) via extrusion-spheronization method using 3.5% w/w of methyl cellulose (Methocel A15LV, MC) as a binding agent, then subjecting to sustained-release coating, and finally forming topiramate pellets with controlled-release function. However, the extrusion-spheronization method is very complicated, both extrusion-spheronization apparatus and coating apparatus are required to fulfill preparation of sustained-release pellet, so that the production process cycle is relatively long, semi-product should be transferred from one apparatus to another, and the use of two manner, i.e., framework and coating, to control the release rate of drug could result in more uncertainty in drug release features.
Thus, it is still in need of providing a combination product comprising phentermine and sustained-release topiramate with simple preparation method, desired drug release, high stability and good drug-release consistency.
Contents of the Invention
With immense amounts of inventive research, the present invention provides a combination product comprising phentermine and sustained-release topiramate, and in comparison with the prior art, this sustained-release pellet of topiramate is free of binding agent in drug layer, and has advantages such as excellent sustained-release effect, simple formulation, easy operation, stable quality, good controllability, and good repeatability. Specifically, the present invention relates to the following aspects.
One aspect of the present invention provides a combination product, which comprises phentermine or salt thereof, and sustained-release pellet of topiramate, in which the sustained-release pellet of topiramate comprises a blank pellet core, a drug layer and a sustained-release coating layer, which is characterized in that the drug layer is free of binding agent.
The drug layer comprises topiramate, and is located on surface of the blank pellet core, and the sustained-release coating layer covers external surface of the drug layer (which structure can be seen in, for example, FIG. 4).
In the combination product according to the present invention, the binding agent can be any binding agents known in the art, including but not being limited to starch slurry, syrup, polyvinylpyrrolidone (povidone, PVP, such as PVP K30), methyl cellulose (MC), ethyl cellulose (EC), highly-substituted hydroxypropyl cellulose (H-HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, gelatin, Arabic gum, and mixtures thereof. When a blank pellet core is loaded with drug without using a binding agent, the time for loading drug is short, and the adhesion degree of pellets is low. In addition, the stability of topiramate drug is significantly improved because the direct contact between topiramate and binding agent is avoided.
In the combination product according to the present invention, the sustained-release coating layer comprises a sustained-release material and other pharmaceutically acceptable excipients, and the sustained-release material can be any sustained-release materials known in the art, including but not being limited to ethyl cellulose, Eudragit NE 30D, Eudragit RS 30D, Eudragit RL30D, and mixtures thereof.
In the combination product according to the present invention, the sustained-release coating layer can further comprises one or more of a plasticizer, a pore former, an anti-adherent, a coloring agent, a light-screening agent, a flavoring, a sweetening agent, etc., in which the plasticizer includes but is not limited to glycerol, propylene glycol, polyethylene glycol, glycerol triacetate, triethyl citrate, phthalates or dibutyl sebacate or a mixture thereof, preferably glycerol triacetate; the pore former includes but is not limited to polyethylene glycols, povidone, sucrose, salts, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose or a mixture thereof, preferably povidone (PVP K30); the anti-adherents includes but is not limited to talc powder, magnesium stearate, aerosil or a mixture thereof, preferably talc powder; the light-screening agent includes but is not limited to titanium dioxide, etc.; the coloring agent includes but is not limited to iron oxide yellow, iron oxide red, carmine, lemon yellow, sunset yellow, indigo blue, etc.; the flavoring agent includes but is not limited to mint essence, lemon essence, orange essence, eucalyptol, syringyl alcohol, etc.; and the sweetening agent includes but is not limited to aspartame, vanillin, sorbitol, mannitol, artificial essences, or a mixture thereof.
In one embodiment of the present invention, the sustained-release coating layer comprises ethyl cellulose and PVP K30.
With lots of experiments, the inventors found that when the sustained-release coating layer comprising ethyl cellulose and PVPK30 in combination is used, the above topiramate drug-loaded pellet has unexpected good effects as compared to coating layers with other sustained-release materials. That is, the topiramate pellet prepared with ethyl cellulose and PVP K30 as sustained-release coating layer material has better stability in drug release, which ensures consistency of drug release in different batches of samples, and the expected sustained-release effects can be achieved without heat treatment after coating. Thus, the coating process is simplified, and the influence of heat treatment after coating on drug release is avoided as well.
Preferably, the weight ratio of ethyl cellulose to PVP K30 is (1:0.20)-(1:0.45), for example (1:0.25)-(1:0.40), for example (1:0.30)-(1:0.35).
In the combination product according to the present invention, the range of weight gain from sustained-release coating (weight percentage of sustained-release material to coating matrix, w/w) can be determined by tests, and generally, the range of weight gain from sustained-release coating is 2%-30%, for example 3%-20%, for example 5%-15%, for example 5%-10%, for example 5%-8%, for example 6%-8%.
In the combination product according to the present invention, the drug layer of sustained-release pellet of topiramate comprises topiramate, and can further comprise other pharmaceutically acceptable excipient(s), such as surfactant(s), disintegrating agent(s), flavoring agent(s), sweetening agent(s), anti-adherent(s), light-screening agent(s), etc. The surfactants include anionic surfactants, cationic surfactant, zwitterionic surfactants, and non-ionic surfactants, including but not being limited to sodium dodecyl sulfate, sodium hexadecanol sulfate, sodium octadecanol sulfate, sodium dodecyl benzene sulfate, dioctyl sodium sulfosuccinate, dihexyl sodium sulfosuccinate, lecithin, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polymer of ethylene oxide and propylene oxide, polyoxyethylene 40 monostearate, polyoxyethylene 50 stearate, oxirane triblock copolymer, epoxypropane triblock copolymer, sorbitan monopalmitate (Span-40), sorbitan monostearate (Span-60), glyceryl monostearate, polyoxyethylene stearate, or mixtures thereof; the disintegrating agents include but are not limited to microcrystalline cellulose, low-substituted hydroxypropyl cellulose sodium, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, pre-gelatinized starch, alginic acid, starch, effervescing disintegrants, or mixtures thereof; the anti-adherents include but are not limited to talc powder, magnesium stearate, aerosil, preferably talc powder; the light-screening agents include but are not limited to titanium dioxide, etc.; the flavoring include but are not limited to mint essence, lemon essence, orange essence, eucalyptol, syringly alcohol, etc.; the sweetening agents include but are not limited to aspartame, vanillin, sorbitol, mannitol, artificial essences, etc.
In one embodiment of the present invention, the drug layer of sustained-release pellet of topiramate consists of topiramate.
In the present invention, the blank pellet cores refer to pellet cores without physiological activity, and may include but not be limited to sugar pellets, microcrystalline cellulose pellets, starch pellets, or silicon dioxide pellets, etc. In one embodiment of the present invention, the blank pellet cores are sugar pellets. The blank pellet core has particle size of 150 μm-1500 μm, for example 250-1000 μm, for example 300-900 μm, for example 400-850 μm, for example 610-750 μm. The blank pellet cores can be purchased, or prepared by conventional means such as extrusion spheronization method, or fluidized bed method.
In the combination product according to the present invention, in the sustained-release pellet of topiramate, topiramate as active ingredient is in an amount of 10%-50%, preferably 15%-45%, more preferably 20%-40%, relative to the total weight of the combined product. In unit preparation, the active ingredient is in an amount of 0.1 mg-500 mg, preferably 1 mg-300 mg, more preferably 10 mg-250 mg, most preferably 10 mg-50 mg, and optimally 23 mg.
In a preferable embodiment of the present invention, the drug layer of sustained-release pellet of topiramate comprises topiramate, the sustained-release coating layer uses ethyl cellulose as sustained-release coating material, PVP K30 as pore former, and the usage amount ratio of ethyl cellulose to PVP K30 is 1:0.20-1:0.45.
In another preferable embodiment of the present invention, the drug layer of sustained-release pellet of topiramate comprises topiramate, the sustained-release coating layer uses ethyl cellulose as sustained-release coating material, PVP K30 as pore former, the usage amount ratio of ethyl cellulose to PVP K30 is 1:0.20-1:0.45, and the range of weight gain from the sustained-release coating is 5%-15%.
In another preferable embodiment of the present invention, the blank pellet cores are sugar pellets, the drug layer of sustained-release pellet of topiramate comprises topiramate, in the sustained-release coating layer, ethyl cellulose is sustained-release coating material, PVP K30 is pore former, the usage amount ratio of ethyl cellulose to PVP K30 is 1:0.20-1:0.45, and the range of weight gain from the sustained-release coating is 5%-15%.
In further another preferable embodiment of the present invention, the blank pellet cores are sugar pellets with particle size of 610 μm-750 μm, the drug layer of sustained-release pellet of topiramate comprises topiramate, in the sustained-release coating layer, ethyl cellulose is sustained-release coating material, PVP K30 is pore former, the usage amount ratio of ethyl cellulose to PVP K30 is 1:0.25-1:0.4, the range of weight gain from the sustained-release coating is 5%-10%.
In further another preferable embodiment of the present invention, the blank pellet cores are sugar pellets with particle size of 610 μm-750 μm, the drug layer of sustained-release pellet of topiramate uses topiramate as active drug, in the sustained-release coating layer, ethyl cellulose is sustained-release coating material, PVP K30 is pore former, the usage amount ratio of ethyl cellulose to PVP K30 is 1:0.25-1:0.4, and the range of weight gain from the sustained-release coating is 5%-8%.
In a special embodiment of the present invention, the blank pellet cores are sugar pellets with particle size of 610 μm-750 μm, the drug layer of sustained-release pellet of topiramate is topiramate, in the sustained-release coating layer, the ethyl cellulose is sustained-release coating material, PVP K30 is pore former, the usage amount ratio of ethyl cellulose to PVP K30 is 1:0.3-1:0.35, and the range of weight gain from the sustained-release coating is 6%-8%.
In the combination product according to the present invention, the sustained-release pellet of topiramate thereof can bring about good therapeutic effect by one administration per 24 h, the in vivo plasma concentration of drug is stable, peak concentration decreases significantly, and good sustained-release effect is fulfilled. The sustained-release pellet of topiramate of the present invention has in vitro release rate of: not greater than 35% within 1 h, between 30% and 60% within 4 h, between 60% and 90% within 8 h, and not less than 90% within 16 h; preferably, not greater than 25% within 1 h, between 35% and 55% within 4 h, between 60% and 85% within 8 h, and not less than 90% within in 16 h; most preferably, not greater than 25% within 1 h, between 35% and 55% within 4 h, between 65% and 85% within 8 h, and not less than 90% within 16 h.
The preferable conditions for determining the release rate in the present invention are in accordance with the first method (for sustained-release preparation or controlled-release preparation) of Release Rate Measurement (Appendix X D) of Part II of Chinese Pharmacopoeia, 2010 Edition, using apparatus as stated in the second method (slurry method) of Dissolution Rate Measurement (Appendix X C) of Part II of Chinese Pharmacopoeia, 2010 Edition, in which samples are taken and analyzed at different specified time points by using water (500 ml) as releasing media, at 37° C. and rotation speed of 100 rpm.
In the combination product according to the present invention, the phentermine or salt thereof is of rapid-release pellet, which can be rapidly released after oral administration.
In the combination product according to the present invention, the salt of phentermine is, for example, hydrochloride, i.e., phentermine hydrochloride.
In the combination product according to the present invention, the immediate-release pellet of phentermine comprises phentermine as active drug, a filling agent and a binding agent, the filling agent includes but is not limited to microcrystalline cellulose, lactose, sucrose, etc.; the binding agent includes but is not limited to starch slurry, syrup, polyvinylpyrrolidone (povidone, PVP, such as PVP K30), methyl cellulose (MC), ethyl cellulose (EC), highly-substituted hydroxypropyl cellulose (H-HPC), hydroxypropyl methyl cellulose (HPMC), sodium carboxymethyl cellulose, gelatin, Arabic gum, sodium alginate, etc. The pellet of phentermine can further comprise other pharmaceutically acceptable excipient(s), such as surfactant(s), disintegrating agent(s), flavoring agent(s), sweetening agent(s), anti-adherent(s), light-screening agent(s), plasticizer(s), etc. The surfactants include anionic surfactants, cationic surfactant, zwitterionic surfactants, and non-ionic surfactants, including but not being limited to sodium dodecyl sulfate, sodium hexadecanol sulfate, sodium octadecanol sulfate, sodium dodecyl benzene sulfate, dioctyl sodium sulfosuccinate, dihexyl sodium sulfosuccinate, lecithin, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, polymer of ethylene oxide and propylene oxide, polyoxyethylene 40 monostearate, polyoxyethylene 50 stearate, oxirane triblock copolymer, epoxypropane triblock copolymer, sorbitan monopalmitate (Span-40), sorbitan monostearate (Span-60), glyceryl monostearate, polyoxyethylene stearate, or mixtures thereof; the disintegrating agents include but are not limited to microcrystalline cellulose, low-substituted hydroxypropyl cellulose sodium, crosslinked polyvinylpyrrolidone, sodium carboxymethyl starch, pregelatinized starch, alginic acid, starch, effervescing disintegrants, or mixtures thereof; the anti-adherents include but are not limited to talc powder, magnesium stearate, aerosil, preferably talc powder; the light-screening agents include but are not limited to titanium dioxide, etc.; the flavoring agents include but are not limited to mint essence, lemon essence, orange essence, eucalyptol, syringly alcohol, etc.; the sweetening agents include but are not limited to aspartame, vanillin, sorbitol, mannitol, artificial essences, etc.; the sweetening agent includes but is not limited to aspartame, vanillin, sorbitol, mannitol, artificial essences, etc.; the plasticizer includes but is not limited to glycerol, propylene glycol, polyethylene glycol, glycerol triacetate, triethyl citrate, phthalates and dibutyl sebacate, etc.
In the combination product according to the present invention, the phentermine as active ingredient in the immediate-release pellet of phentermine, is in an amount of 1%-30%, preferably 2%-20%, more preferably 3%-15%, relative to the total weight of phentermine pellet. Unit preparation can have active ingredient in an amount of 1 mg-40 mg, preferably 2 mg-35 mg, more preferably 3 mg-30 mg, most preferably 3.5 mg-20 mg, optimally 3.75 mg-15 mg. The amount or dose of phentermine refers to amount or dose of phentermine per se, and when salt of phentermine is used, conversion should be performed, for example, when the dose of phentermine is 3.75 mg, which corresponds to 4.92 mg of phentermine hydrochloride.
In the combination product according to the present invention, the immediate-release pellet of phentermine has a dissolution rate of at least 80% or more of labeled content dissolved within 30 min; preferably, the dissolution rate is at least 80% or more of labeled content dissolved within 15 min; and most preferably, the dissolution rate is at least 80% or more of labeled content dissolved within 5 min.
The immediate-release pellet of phentermine as prepared in the present invention has a particle size of 150 μm-1500 μm, preferably 300 μm-1000 μm, more preferably 400 μm-850 μm, most preferably 610 μm-750 μm.
The pellet of phentermine and the pellet of topiramate in the present invention can be further processed to form various suitable preparations, for example, can be loaded in capsules to form phentermine-topiramate capsules, or be tableted to form tablets.
The combination product according to the present invention is capsule or tablet. In one embodiment of the present invention, the combination product is capsule.
In the combination product according to the present invention, the content of topiramate in unit preparation can be 1 mg-500 mg, the content of phentermine can be 1 mg-40 mg; preferably, the content of topiramate is 5 mg-300 mg, the content of phentermine is 2 mg-35 mg; more preferably, the content of topiramate is 10 mg-250 mg, the content of phentermine is 3 mg-30 mg; most preferably, the content of topiramate is 20 mg-100 mg, the content of phentermine is 3.5 mg-20 mg; optimally, the content of topiramate is 23 mg-92 mg, the content of phentermine is 3.75 mg-15 mg.
In one embodiment of the present invention, unit preparation comprises 23 mg of topiramate, and 3.75 mg of phentermine; in another embodiment of the present invention, unit preparation comprises 46 mg of topiramate, and 7.5 mg of phentermine; in further another embodiment of the present invention, unit preparation comprises 92 mg of topiramate, and 15 mg of phentermine.
Another aspect of the present invention relates to a method for preparing a sustained-release pellet of topiramate in the combination product according to the invention, the method comprising the following procedure:
a) dissolving ingredients of the drug layer with suitable amount of solvent, and coating a blank pellet core with the obtained drug solution to give a drug-loaded pellet;
b) coating the drug-loaded pellet obtained in step a) with ingredients of sustained-release coating layer.
In the preparation method according to the present invention, the step b) comprises the following steps:
dissolving ingredients of the sustained-release coating layer in a solvent, and coating the drug-loaded pellet obtained in step a) with the resultant solution.
In an embodiment of the present invention, the method for preparing a sustained-release pellet of topiramate comprises the following steps:
a) dissolving the topiramate and optional other excipients of drug layer with suitable amount of solvent under the condition of heating and stirring, placing blank pellet core in a fluidized bed coating pan for marumerization, and coating the blank pellet core with the obtained solution under stirring to give drug-loaded pellet.
b) dissolving a sustained-release coating material and optional other excipients of sustained-release coating layer in a solvent under the condition of heating and stirring, mixing homogeneously, passing through a 100-mesh sieve, to obtain a sustained-release coating solution;
c) spraying the surface of the drug-loaded pellet with the sustained-release coating solution in a fluidized bed to give a sustained-release pellet of topiramate.
In the preparation method according to the present invention, the solvent is water, ethanol, acetone, propylene glycol, chloroform or a mixture thereof, for example, the solvent is a mixture of water and ethanol, for example, can be 50% ethanol water solution, 70% ethanol water solution, 95% ethanol water solution.
In one specific embodiment of the present invention, the method for preparing topiramate pellet comprises:
a) Topiramate is provided as main drug, dissolved with ethanol solution to prepare a drug-loading and coating solution with concentration of 15-25% (w/v), preferably 20% (w/v). A blank pellet core is placed in a fluidized bed coating pan for one step pelletization, and the above drug-loading and coating solution is used for drug loading and coating under stirring to obtain a drug-loaded pellet core.
b) Ethyl cellulose as sustained-release coating material is dissolved in ethanol solution to achieve a concentration of 3-8% (w/v), preferably 5-7% (w/v), and added with a suitable amount of specific pore former, PVP K30, then dissolved under the condition of heating and stirring, stirred homogenously, after passing through 100-mesh sieve, the obtained solution is atomized and sprayed on the drug-loaded pellet core with active drug layer of topiramate in a fluidized bed bottom-spraying coating pan to conduct sustained-release coating.
The process parameters for drug-loading and coating and sustained-release coating in the fluidized bed can be regulated according to practical situations, and preferable process parameters are as follows:
Drug-loading and coating—inlet air temperature is 50-70° C. (to keep pan internal temperature at 40±2° C.); inlet air pressure is 0.3-0.5 bar; atomization pressure is 1.0-2.0 bar; solution spray rate is 5-15 g/min.
Sustained-release coating—inlet air temperature is 40-45° C. (to keep pan internal temperature at 30-35° C.); inlet air pressure is 0.3-0.5 bar; atomization pressure is 1.0-2.0 bar; solution spray rate is 3-12 g/min.
In the present invention, the pellet of phentermine can be prepared by conventional methods for preparation of pellet, such as centrifugation pelletization, extrusion spheronization, and fluidized bed drug-loading and coating method.
Specifically, the following method can be used for the preparation: 400 g of blank sucrose pellet cores is placed in a centrifugation pelletizer, phentermine or salt thereof is weighed, added to a feeder of the pelletizer, and homogeneously laminated on the cores by spraying with binding agent and other excipients, thereafter, the obtained product are taken out, dried to obtain immediate-release drug-loaded pellets of phentermine. The following method can also be used for the preparation: phentermine or salt thereof is weighed, homogeneously mixed with a filling agent and other excipients, added with a binding agent to obtain a suitable soft material, the soft material is placed in a spheronizator, extruded and spheronized, and the obtained pellets are dried, sieved, to obtain rapid-release pellets of phentermine. The following method can also be used for the preparation: phentermine or salt thereof and a suitable amount of binding agent and other excipients are weighed, and dissolved with a suitable solvent to obtain a drug-containing coating solution. Blank pellet cores are weighed, placed in a fluidized bed bottom spray coating pan, and the drug-containing coating solution is sprayed in manner of bottom spray to the surface of the blank pellet cores when the blank pellet cores are in fluidized state. The materials are further fluidized for 5 min after drug-loading, then taken out to obtain immediate-release drug-loaded pellets of phentermine.
The present invention further relates to a use of the combination product of the present invention in manufacture of a medicament for reducing body weight, reducing blood fat, lowering blood pressure, and treatment of metal or nervous diseases.
The present invention further relates to a use of the combination product of the present invention in manufacture of a medicament for treatment of hyperlipidemia, hypertension, diabetes, or coronary heart disease.
The present invention further relates to a method for realizing weight loss, blood fat reduction, antihypertension and treatment of mental or nervous diseases in a subject, comprising administering the subject in such need a therapeutically effective amount of the combination product of the present invention.
In the present invention, the unit preparation refers to a physically dispersed unit, which is suitably used as unit dose for treatment of individual. That is, the composition is formulated as dispersive dose units, each contains active agent in amount of predetermined “unit dose”, and the amount is calculated so as to bring about expected therapeutic effects together with the required pharmaceutically acceptable carrier.
In the present invention, the sustained-release pellet can also be called as controlled-release pellet or sustained-release/controlled-release microsphere.
In the present invention, the term “combination product” refers to a product in which phentermine or salt thereof and topiramate are used in combination. The combination product can be a pharmaceutical composition comprising of phentermine or salt thereof and topiramate as two active ingredients, or two pharmaceutical compositions which are prepared with phentermine or salt thereof and topiramate, respectively. Preferably, the two separate pharmaceutical compositions are: a immediate-release preparation comprising phentermine or salt thereof, preferably immediate-release pellet; and a sustained-release or controlled-release preparation comprising topiramate, preferably sustained-release pellet. In the combination product, the phentermine or salt thereof and topiramate can be simultaneously or separately administered to the individual in need of such treatment; or phentermine or salt thereof is administered first, then topiramate is administered after an interval of time; or topiramate is administered first, then phentermine or salt thereof is administered after an interval of time; the interval of time can be determined according to the pharmacologic or pharmacokinetic features of the two drugs.